The pressure‑temperature behavior of anhydrous caffeine’s two polymorphs—form II (monoclinic) and form I (trigonal)—was characterized by high‑resolution powder diffraction, electron microscopy, differential scanning calorimetry and high‑pressure thermal analysis. Measured transition enthalpies are 19 J g⁻¹ for the solid‑solid conversion and 109 J g⁻¹ for melting of form I. Direct application of the Clapeyron equation to these state functions yields linear equilibrium relations with slopes of dP/dT = 4.15 MPa K⁻¹ for the I-II equilibrium and 2.6 MPa K⁻¹ for the I‑L equilibrium, values that match the direct measurements at different pressures and temperatures in this study and in the literature. The resulting phase diagram shows divergent I-II and I‑L lines with increasing pressure, placing caffeine in Bakhuis-Roozeboom’s case 2 (overall enantiotropy) and locating the I‑II‑L triple point at negative pressure, thus metastable. Form I consistently has a larger specific volume than form II, and the volume change on melting follows the typical VL/VS ratio of about 1.11 for organic solids. The close agreement between experiment and Clapeyron‑based (topological) predictions demonstrates that the topological method correctly captures polymorphic stability across broad pressure and temperature ranges.

Broparestrol has been used as a drug to treat acne in the form of a mixture of its two stereoisomers. Although it has been withdrawn from the market, the binary system is rich in polymorphism and understanding the phase behaviour of the binary system involving the E- and Z-isomers is challenging. Physical mixtures do not immediately give rise to equilibrium phase behaviour, whereas recrystallization often leads to metastable phases and the appearance of stable phases can take years. A new polymorph of E-broparestrol has been found crystallizing in a monoclinic unit cell, space group P21/c, with lattice parameters a = 5.6079(4) & Aring;, b = 16.1206(10) & Aring;, c = 20.250 (1) & Aring;, beta = 100.569(4)degrees, Vcell = 1799.6(2) & Aring;3, and Z = 4. This polymorph, IE, is stable at high temperatures, whereas the published form, IIE, is stable at room temperature. In the case of Z-broparestrol polymorphism has been observed too; however, it has so far only occurred within the binary phase diagram, and it has not been possible to isolate the new polymorph of Z-broparestrol, IIZ. Through the phase behaviour in the binary system, it could be determined that the new Z polymorph, IIZ, behaves monotropically in relation to the known triclinic polymorph of the Z-isomer, IZ. Nothing is known about its structure, and it is therefore not clear yet whether IIZ may possess a stable domain under pressure. A stable temperature-composition phase diagram of the binary system containing E- and Z-broparestrol is proposed.

The availability of sufficient amounts of form I of benzocaine has led to the investigation of its phase relationships with the other two existing forms, II and III, using adiabatic calorimetry, powder X-ray diffraction, and high-pressure differential thermal analysis. The latter two forms were known to have an enantiotropic phase relationship in which form III is stable at low-temperatures and high-pressures, while form II is stable at room temperature with respect to form III. Using adiabatic calorimetry data, it can be concluded, that form I is the stable low-temperature, high-pressure form, which also happens to be the most stable form at room temperature; however, due to its persistence at room temperature, form II is still the most convenient polymorph to use in formulations. Form III presents a case of overall monotropy and does not possess any stability domain in the pressure–temperature phase diagram. Heat capacity data for benzocaine have been obtained by adiabatic calorimetry from 11 K to 369 K above its melting point, which can be used to compare to results from in silico crystal structure prediction.

The crystal structure of the low-temperature form II of butamben has been solved in a P2(1)/c space group very similar to that of form I. Form II possesses virtually the same packing as that of the high-temperature form I, and the dimorphism is mainly represented by a small discontinuous change in the size of the unit cell and by a difference in the enthalpy. Because of the small enthalpy difference between the two polymorphs of 375 J.mol(-)(1), it will be difficult to predict the change in the stability hierarchy by computer-aided methods. The pressure-temperature phase diagram, constructed using volume and enthalpy differences between the two phases at ordinary pressure, corresponds to a case of overall enantiotropy, as the I-II and I-L equilibrium lines diverge with increasing pressure. This conclusion is confirmed by the experimental pressure-temperature phase diagram obtained with differential thermal analysis measurements under pressure.

Morniflumate diniflumate, a molecular compound involving niflumic acid and its beta-morpholino ethyl ester (morniflumate) in the mole ratio 2:1, is found to crystallize in a triclinic P - 1 space group with a unit-cell volume of 2203.4(5) angstrom 3. It is a cocrystal between a morniflumate+ niflumate- salt and a neutral niflumic acid molecule. The co-crystalline salt forms endothermically with a positive excess volume and it melts incongruently at 382.3(8) K. Differential scanning calorimetry executed at heating rates above 20 K.min- 1, leads to congruent melting at 387.8(9)K with an enthalpy change of Delta fusH = 80(2) J g-1. The rare occurrence that incongruent and congruent melting can be observed for the same cocrystal may be due to the conformational versatility of the niflumic acid molecule and its slow conversion between the different conformations due to weak intramolecular hydrogen bonding.

The crystal structures of dimorphic benzylthiouracil, a drug against hyperthyroidism, have been redetermined and the atom coordinates of the two independent molecules of form I have been obtained for the first time. The dimorphism convincingly demonstrates the conformational versatility of the benzylthiouracil molecule. It has been established through calorimetric studies that the low-temperature form II transforms endothermically (Delta H-II -> I = 5.6(1.5) J g(-1)) into form I at 405.4(1.0) K. The high-temperature form I melts at 496.8(1.0) K (Delta H-I -> L = 152.6(4.0) J g(-1)). Crystallographic and thermal expansion studies show that form II is denser than form I, leading to the conclusion that the slope of the II-I equilibrium curve in the pressure-temperature phase diagram is positive. It follows that this dimorphism corresponds to a case of overall enantiotropic behaviour, which implies that both solid phases possess their own stable phase region irrespective of the pressure. Moreover, form II is clearly the stable polymorph under ambient conditions.

The structure of the metastable form II of 2-bromobenzophenone, obtained by crystallization from the melt, has been determined by powder X-ray diffraction. Form II has been solved in the centrosymmetric monoclinic space group P2(1)/c with a = 8.4896(19) angstrom, b = 6.5438(8) angstrom, c = 20.253(1) angstrom; beta = 104.452(6)degrees, and Z = 4 (Z' = 1) at 200 K. Both form I and form II contain a multitude of aromatic interactions, and the strength and direction of these interactions could only be interpreted with the support of the thermal-expansion tensors. Both forms exhibit, unexpectedly, uniaxial negative thermal expansion, while hydrogen bonding does not play a significant role in either of these two structures. It appears to be the first time in the literature that uniaxial negative thermal expansion may be caused by aromatic interactions. Thermodynamic properties at normal and high pressure have been determined for the stable and metastable phases, and a pressure-temperature phase diagram has been constructed. While the metastable form behaves monotropically with respect to the stable form under ambient conditions, the phase relationship becomes enantiotropic at high pressure, providing a clear example of phase behavior in which the densest form is not the most stable form under ambient conditions.

The volume change on melting is a rarely studied quantity and it is not well understood even if it must reflect the changes in interaction between the solid and the liquid state. It is part of the solid-state information for materials and pharmaceuticals and it is important for the reliability of polymorph stability study results. Using the crystal structure of monoclinic tetrazepam at 150 K and at room temperature, in addition to powder X-ray diffraction as a function of the temperature, the specific volume of tetrazepam has been determined over a large temperature domain. In combination with a pressure-temperature curve for the melting of tetrazepam, its volume change on melting could be determined. With this information and previous data from the literature, the assumption that the volume of the solid increases on average with 11% on melting has been investigated. It can be concluded that this value is not constant; however so far, no simple relationship has been found to relate the solid state to its volume change on melting and using 11% remains best practice. A comparison of the tetrazepam crystal structure with diazepam and nordiazepam has been provided too.

The formation of co-crystals is often unexpected; however, the Buckminster fullerene, for which many solvates are known, is an excellent system to study this tendency.

Since the early nineties countless publications have reported promising medicinal applications for [60]fullerene (C60) related to its unparalleled affinity towards free radicals. Yet, until now no officially approved C60-based drug has reached the market, notably because of the alleged dangers of C60. Nevertheless, since the publication of the effects of C60 on the lifespan of rodents, a myriad of companies started selling C60 worldwide for human consumption without any approved clinical trial. Nowadays, several independent teams have confirmed the safety of pure C60 while demonstrating that previously observed toxicity was due to impurities present in the used samples. However, a purity criterion for C60 samples is still lacking and there are no regulatory recommendations on this subject. In order to avoid a public health issue and for regulatory considerations, a quality-testing strategy is urgently needed. Here we have evaluated several analytical tools to verify the purity of commercially available C60 samples. Our data clearly show that differential scanning calorimetry is the best candidate to establish a purity criterion based on the sc-fcc transition of a C60 sample (Tonset ≥ 258 K, ∆sc-fccH ≥ 8 J g−1).

X-ray measurements reveal a tenfold symmetry in a single crystal of fullerene C60 grown from a n-hexane solution. Among various hypotheses, that of a quasicrystal is considered. It is generally admitted that the crystalline structure of fullerene C60 is face-centered cubic at room temperature [I], but a hexagonal close-packed lattice has also been proposed [2]. The structure seems also to depend on the presence of some amount of Cm [3] or on the solvent from which the solid samples have been crystallized [4]. For instance, Hawkins et aJ.[4] assigned a P63/m space group to C60 single crystals grown from n-hexane solutions, that is a structure which is neither hexagonal nor cubic closest-packed. On the other hand, Fleming et al. [5] have flescribed a pseudotenfold symmetry for crystals of C60 or Cm cocrystallized with n-pentane. They explain their results in terms of twinning of monoclinic crystals. We initially aimed to investigate the influence of solvents on the structure of crystallized C60 and the observations we made on crystals grown from n-hexane led us to analogous apparent tenfold morphologies but a different assignment seems necessary. (*) URA 1110, CNRS. (**) URA D 1104, CNRS. (***) URA 233, CNRS. 2 JOURNAL DE PHYSIQUE I N°1

The (010) plane of the C60·2CBrClH2 monoclinic (C2/m) co-crystal with both molecular entities, C60 and CBrClH2, orientationally ordered.

Spironolactone form I melts at about 70 degrees lower than form II, which is very unusual for two co-existing polymorphs. The phase relationships involving this unprecedented case of dimorphism have been investigated by constructing a topological pressure-temperature phase diagram. The transition from polymorph I to polymorph II is unambiguously exothermic while it is accompanied with an increase in the specific volume. This indicates that the dP/dT slope of the I-II equilibrium curve is negative. The convergence of the melting equilibrium lines at high pressure leads to a topological P-T diagram in which polymorph I possesses a stable phase region at high pressure. Thus, forms I and II are monotropically related at ordinary pressure and turn to an enantiotropic relationship at high pressure. Given that polymorph I is the densest form, it negates the rule of thumb that the densest form is also the most stable form at room temperature, similar to the case of paracetamol.

Thermodynamics is often considered difficult to understand due to extensive use of mathematics. In the present paper, a graphical approach will be used to explain the origin of phase diagrams starting from the fundamental equation of thermodynamics dU = Tds − Pdv defined by J.W. Gibbs. The characteristic variables of this equation are the specific entropy s and the specific volume v, which lead in a straightforward way to s-v phase diagrams. It will be demonstrated through monotonicity of the internal energy curves of the different phases of the system and graphical Legendre transformations how pressure-entropy (P-s) and temperature-volume (T-v) phase diagrams are linked to s-v phase diagrams and how the latter two phase diagrams are related to pressure-temperature (P-T) phase diagrams.

Understanding the polymorphic behavior of active pharmaceutical ingredients is important for formulation purposes and regulatory reasons. Metacetamol is an isomer of paracetamol and it similarly exhibits polymorphism. In the present article, it has been found that one of the polymorphs of metacetamol is only stable under increased pressure, which has led to the conclusion that metacetamol like paracetamol is a monotropic system under ordinary (= laboratory) conditions and that it becomes enantiotropic under pressure with the I-II-L triple point coordinates for metacetamol TI-II-L = 535 ± 10 K and PI-II-L = 692 ± 70 MPa. However, whereas for paracetamol the enantiotropy under pressure can be foreseen, because the metastable polymorph is denser, in the case of metacetamol this is not possible, as the metastable polymorph is less dense than the stable one. The existence of the stability domain for the less dense polymorph of metacetamol can only be demonstrated by the construction of the topological phase diagram as presented in this article. It is a delicate interplay between the specific volume differences and the enthalpy differences causing the stability domain of the less dense polymorph to be sandwiched between the denser polymorph and the liquid. Metacetamol shares this behavior with bicalutamide and fluoxetine nitrate.

The phase behavior of pharmaceuticals is important for regulatory requirements and dosage form development. Racemic fluoxetine nitrate possesses two crystalline forms for which initial measurements indicated that they have a monotropic relationship with form I the only stable form. By constructing the topological pressure-temperature phase diagram, it has been shown that unexpectedly form II has a stable domain in the phase diagram and can be easily obtained by heating and grinding. The pressure necessary to obtain form II is only 11 MPa, which is much lower than most pressure used for tableting in the pharmaceutical industry.

We demonstrate that solvates of fullerene C60 form very predictable structures with finely tunable properties through the choice of the second component or solvent. Cubic co-crystals of C60·12CCl2Br2 and C60·12CBr2(CH3)2 were grown at room temperature in saturated solutions of fcc C60 and the respective solvents (with C2v molecular symmetry) They are unstable in air and transform spontaneously into the hexagonal co-crystals C60·2CCl2Br2 or C60·2CBr2(CH3)2. Whereas, the cubic co-crystals have positive excess volumes (+2% and +5%, respectively), the stable hexagonal crystals, for which structures are given for the first time, possess negative excess volumes (−5% and −4.3%, respectively). The unit-cell volumes for both cubic and hexagonal co-crystals depend exclusively on the van-der-Waals volumes of the constituents and this correlation has been confirmed using previously published data.

Two polymorphs of the 1:1 fumarate salt of 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid 4-bromophenyl ester, developed for the treatment of cognitive symptoms of schizophrenia and Alzheimer disease, have been characterized. The 2 crystal structures have been solved, and their phase relationships have been established. The space group of form I is P2(1)/c with a unit-cell volume of 1811.6 (5) angstrom(3) with Z = 4. The crystals of form I were 2-component nonmerohedral twins. The space group of form II is P2(1)/n with a unit-cell volume of 1818.6 (3) angstrom(3) with Z = 4. Relative stabilities have been inferred from experimental and topological P-T diagrams exhibiting an overall enantiotropic relationship between forms I and II although the solid-solid transition has never been observed. The slope of the I-II equilibrium in the P-T diagram is negative, form II is the stable phase below the solid-solid transition temperature of 371 K, and form I exhibits a stable melting equilibrium. The I-II transition temperature has been obtained from the intersection of the sublimation curves of the 2 solid forms. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

The trimorphism of the active pharmaceutical ingredient piracetam is a famous case of polymorphism that has been frequently revisited by many researchers. The phase relationships between forms I, II, and III were ambiguous because they seemed to depend on the heating rate of the DSC and on the history of the samples or they have not been observed at all (equilibrium II–III). In the present paper, piezo-thermal analysis and high-pressure differential thermal analysis have been used to elucidate the positions of the different solid–solid and solid–liquid equilibria. The phase diagram, involving the three solid phases, the liquid phase and the vapor phase, has been constructed. It has been shown that form III is the high-pressure, low-temperature form and the stable form at room temperature. Form II is stable under intermediary conditions and form I is the low pressure, high temperature form, which possesses a stable melting point. The present paper demonstrates the strength of the topological approach based on the Clapeyron equation and the alternation rule when combined with high-pressure measurements.